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. 2013 May;34(5):1519.e5-12.
doi: 10.1016/j.neurobiolaging.2012.10.003. Epub 2012 Oct 27.

Repeat expansions in the C9ORF72 gene contribute to Alzheimer's disease in Caucasians

Martin A Kohli  1 , Krista John-Williams, Ruchita Rajbhandary, Adam Naj, Patrice Whitehead, Kara Hamilton, Regina M Carney, Clinton Wright, Elizabeth Crocco, Harry E Gwirtzman, Rosalyn Lang, Gary Beecham, Eden R Martin, John Gilbert, Michael Benatar, Gary W Small, Deborah Mash, Goldie Byrd, Jonathan L Haines, Margaret A Pericak-Vance, Stephan Züchner
Affiliations

Repeat expansions in the C9ORF72 gene contribute to Alzheimer's disease in Caucasians

Martin A Kohli et al. Neurobiol Aging. 2013 May.

Abstract

Recently, a hexanucleotide repeat expansion in the C9ORF72 gene has been identified to account for a significant portion of Caucasian families affected by frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Given the clinical overlap of FTD with Alzheimer's disease (AD), we hypothesized that C9ORF72 expansions might contribute to AD. In Caucasians, we found C9ORF72 expansions in the pathogenic range of FTD/ALS (>30 repeats) at a proportion of 0.76% in AD cases versus 0 in control subjects (p = 3.3E-03; 1182 cases, 1039 controls). In contrast, no large expansions were detected in individuals of African American ethnicity (291 cases, 620 controls). However, in the range of normal variation of C9ORF72 expansions (0-23 repeat copies), we detected significant differences in distribution and mean repeat counts between Caucasians and African Americans. Clinical and pathological re-evaluation of identified C9ORF72 expansion carriers revealed 9 clinical and/or autopsy confirmed AD and 2 FTD final diagnoses. Thus, our results support the notion that large C9ORF72 expansions lead to a phenotypic spectrum of neurodegenerative disease including AD.

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Conflict of interest statement

5.1 Disclosure Statement

The authors of this manuscript have no potential conflicts of interests related to this work.

Figures

Fig. 1
Fig. 1. Overview of families and sporadic individuals affected by C9ORF72 expansions
(A) FTD reclassified index case/family, (B) AD/ALS families, (C) AD family and sporadic/isolated AD cases. Sporadic is defined as a single case with recorded family history, whereas an isolated case did not have family history available. Gender is not provided for privacy reasons.
Fig. 2
Fig. 2. Histopathological findings in C9ORF72 expansion carriers
(A – C) The index case in family 6 showed classic AD changes including (A) neuronal loss and plaques (B) tau positive threads and tangles, and (C) amyloid plaques throughout the neocortex and hippocampus. (D – F) The index patient from family 2 showed (D) microvacuolation in the frontal cortex, (E) ubiquitin-immunoreactive intracellular inclusions in the hippocampus, and (F) cortical extracellular amyloid plaques. For more details see supplementary data.
Fig. 3
Fig. 3
(A and B) Histograms of C9ORF72 repeat copies in AD case-control collections of (A) European and (B) African American descent. (C and D) Histograms of C9ORF72 repeat copies compared between European and African American ethnicities in (C) cases and (D) controls.
See this image and copyright information in PMC

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